Estrogens play an important major role in existing methods of hormonal contraception. For contraception estrogens are commonly used together with a progestogen, e.g. levonorgestrel, desogestrel, norethisterone, cyproterone acetate, dienogest. The estrogens are needed for inhibiting follicle maturation and ovulation, but in addition they replace the endogenous ovarian secretion of estradiol which is suppressed to a major extent by the administration of a hormonal contraceptive. This replacement is important for preventing estrogen deficiency and for maintaining an artificial menstrual cycle and other genital functions.
Endogenous and exogenous estrogens fulfil important central nervous and metabolic functions in the female organism: normal estrogen levels make a decisive contribution to a woman's well-being. Notwithstanding the widespread use of estrogens in hormonal contraceptives, there are still some unsolved problems. Known estrogens, in particular the biogenic estrogens (i.e. estrogens that occur naturally in the human body), are eliminated from the blood stream very quickly. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active. This is particularly undesirable in contraceptive methods.
The most important synthetically altered estrogenic steroid is 17α-ethinyl estradiol (EE). This estrogen is dominant in oral hormonal contraception. Apart from EE, mestranol has been used in a few cases; mestranol is a “prodrug” that is metabolised to EE in the organism. The liver is a target organ for estrogens. The secretion activity that is affected by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. The strong hepatic estrogenicity of ethinyl estradiol and diethylstilbestrol (DES), especially their effects on haemostasis factors, may explain why these synthetic estrogens have been associated with the enhanced risk of thromboembolism. Other undesirable side-effects that have been reported in relation to the use of synthetic estrogens include fluid retention, nausea, bloating, cholelithiasis, headache and breast pain.
The aforementioned deficits are of considerable clinical significance when commonly known biogenic or synthetic estrogens are applied. Consequently, there is an as yet unmet need for estrogens that do not display these deficits and which can suitably be employed in contraceptive methods for females because of their ability to (a) reliably suppress follicle maturation and ovulation and to (b) effectively replace the endogenous ovarian secretion of 17β-estradiol.